Pulse Pressure Variance (PPV)-Guided Fluid Management in Adult Patients Undergoing Supratentorial Tumor Surgeries: A Randomized Controlled Trial.

Objective Appropriate fluid management in neurosurgery is critical due to the risk of secondary brain injury. Determination of volume status is challenging with static variables being unreliable. Goal-directed fluid therapy with dynamic variables allows reliable determination of fluid responsiveness and promises better outcomes. We aimed to compare the intraoperative fluid requirement between conventional central venous pressure (CVP)-guided and pulse pressure variance (PPV)-guided fluid management in supratentorial tumor surgeries. Materials and Methods This prospective, randomized, double-blind, single-center trial was conducted with 72 adults undergoing supratentorial tumor surgery in a supine position. Patients were divided into two groups of 36 patients each receiving CVP- and PPV-guided fluid therapy. The CVP-guided group received boluses to target CVP greater than 8 mm Hg along with hourly replacement of intraoperative losses and maintenance fluids. The PPV-guided group received boluses to target PPV less than 13% in addition to maintenance fluids. Total intraoperative fluids administered and the incidence of hypotension was recorded along with the brain relaxation score. Postoperatively, serum lactate levels, periorbital and conjunctival edema, as well as postoperative nausea and vomiting were assessed. Statistical Analyses All statistical analyses were performed with Statistical Package for Social Sciences, version-20 (SPSS-20, IBM, Chicago, Illinois, United States). To compare the means between the two groups (CVP vs. PPV), independent samples t -test was used for normal distribution data and Mann-Whitney U test for nonnormal distribution data. The chi-square test or Fischer's exact test was used for categorical variables. Results The CVP group received significantly more intraoperative fluids than the PPV group (4,340 ± 1,010 vs. 3,540 ± 740 mL, p < 0.01). Incidence of hypotension was lower in the PPV group (4 [11.1%] vs. 0 [0%], p = 0.04). Brain relaxation scores, serum lactate levels, periorbital and conjunctival edema, and incidence of postoperative nausea and vomiting were comparable between the groups. Conclusion The requirement for intraoperative fluids was less in PPV-guided fluid management with better hemodynamic stability, adequate brain conditions, and no compromise of perfusion.

Folic acid-chitosan functionalized polymeric nanocarriers to treat colon cancer.

In the present study, polymeric nanoparticles loaded with IRI and quercetin, a p-gp inhibitor, were developed to target folate receptors expressed by colon cancer cells for oral targeted delivery. This work reports the development of PNPs with an entrapment efficiency of 41.26 ± 0.56 % for IRI and 55.83 ± 4.51 for QT. PNPs were further surface modified using chitosan-folic acid conjugates for better targetability to obtain folic acid-chitosan coated nanoparticles. DLS and FeSEM revealed particles in the nanometric size range with spherical morphology, while FTIR and DSC provided details on their structure and encapsulation. In vitro drug release studies confirmed a sustained release pattern of IRI and QT, while cell line studies confirmed the superiority of C-FA-PNPs when tested on Caco2 cells. Pharmacodynamic studies in colon cancer induced rats showed similar efficacy for PNPs and C-FA-PNPs. Further examination from a bio-distribution study in healthy rats, revealed the failure of C-FA-PNPs to deliver the drugs to the colon adequately, while the PNPs improved the available concentration of IRI at the colon by almost 1.8 folds when compared to the available marketed product. Hence, the developed PNP formulation sticks out as a plausible substitute for the intravenous dosage forms of IRI which have been conventionally prevailing.

Evaluation of the Role of Preoperative Oral Amisulpride as Part of a Multimodal Antiemetic Prophylaxis Regime on Postoperative Nausea and Vomiting in Patients Undergoing Craniotomy: A Prospective, Double-Blind, Randomized, Placebo-controlled Study.

BACKGROUND: Patients undergoing craniotomy are at high risk for postoperative nausea and vomiting (PONV) despite the use of prophylactic antiemetics. We hypothesized that a single preoperative oral dose of amisulpride as part of a multimodal antiemetic regimen would decrease the incidence of PONV in patients undergoing craniotomy for intracranial tumor surgery. METHODS: Adult patients scheduled for elective craniotomy requiring general anesthesia were enrolled and randomized to receive either oral amisulpride 25 mg or placebo 2 hours before surgery in addition to our institution's usual antiemetic regimen. The primary outcome of the study was the incidence of nausea and/or vomiting during the first 24 hours postoperatively. Secondary outcomes included severity of nausea, use of rescue antiemetic medications, and treatment-related adverse events. RESULTS: A total of 100 patients were included in the analysis. More patients in the amisulpride group had no episodes of nausea (90% vs. 40%; P<0.001) and no episodes of vomiting (94% vs. 46%; P<0.001) compared with the placebo group. The severity of nausea was lower in the amisulpride group than in the control group in the first 4 hours after surgery (P<0.05), and fewer patients receiving amisulpride required rescue antiemetics (P<0.001). The incidence of treatment-related adverse events was similar between groups. CONCLUSIONS: A single preoperative oral dose of amisulpride 25 mg as a component of a multimodal antiemetic regimen decreased the incidence and severity of PONV in patients undergoing craniotomy for intracranial tumor surgery, with no adverse effects.

Fullerenes for the treatment of cancer: an emerging tool.

Cancer is a most common cause of mortality globally. Available medicines possess severe side effects owing to their non-specific targeting. Hence, there is a need of an alternative in the healthcare system that should have high efficacy with the least side effects, also having the ability to achieve site-specific targeting and be reproducible. This is possible with the help of fullerenes. Fullerenes are having the unique physicochemical and photosensitizer properties. This article discusses the synthesis, functionalization, mechanism, various properties, and applications of C60 fullerenes in the treatment of cancer. The review article also addresses the various factors influencing the activity of fullerenes including the environmental conditions, toxicity profile, and future prospective.

Development and Validation of High-Performance Liquid Chromatography Method for the Quantification of Remdesivir in Intravenous Dosage Form.

Corona virus disease 2019 (COVID-19) has posed a mounting threat to public health with worldwide outbreak caused by a novel virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recently, remdesivir (RDV) has been approved by Food and Drug Administration (FDA) for treating COVID-19 patients ≥12 years old requiring hospitalization. To the best of our knowledge, a simple method to estimate RDV in the pharmaceutical formulations using high-performance liquid chromatography (HPLC) is still unexplored, highlighting the need for a precise analytical method for its quantification. The prime purpose of the current investigation was to develop and validate a well-grounded HPLC method for quantification of RDV in pharmaceutical formulations. The best chromatogram was obtained by means of an Inertsil ODS-3V column using a mobile phase of milli-Q water modified to pH 3.0 with o-phosphoric acid and acetonitrile (50:50, % v/v) at a flow rate of 1.2 mL/min and wavelength of detector set at 246 nm with retention time being achieved at 6.0 min. The method was validated following International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q2 (R1) guidelines for various parameters such as specificity and selectivity, system suitability, linearity, precision, accuracy, limits of detection and quantification, and robustness. The method developed for the quantification of RDV was found to be linear in the concentration range of 25-2,500 ng/mL with limit of detection and limit of quantification of 1.95 and 6.49 ng/mL, respectively. Assay value of 102% ± 1% was achieved for marketed injectable dosage form when estimated by the validated method. Therefore, in this study a simple, rapid, sensitive, selective, accurate, precise, and robust analytical method was developed and validated for the quantification of RDV using HPLC. The established method was successfully employed for quantification of RDV in marketed pharmaceutical formulation.

A rapid method for solubilization of chimeric human interferon regulatory factor-1 (IRF-1) protein in Escherichia coli.

Interferon regulatory factor-1 (IRF-1) is a vertebrate transcription factor that plays significant roles in cell cycle regulation, anti-viral response, tumor suppression and immune response. High-level expression of recombinant IRF-1 at 37 °C leads to the formation of insoluble aggregates (insoluble fraction) in Escherichia coli (E. coli), which usually devoid of biological activity. In this study, we use chemical additives such as mannitol, proline, L-arginine and CTAB (cetyl trimethly ammonium bromide) at the recommended concentration during cell lysis to aid in solubility at 37 °C. The use of additives resulted in the increased solubility of the recombinant glutathione S-transferase-linked human IRF-1, with L-arginine being most effective. Here, we developed an efficient process for the manufacturing of soluble IRF-1 with the aid of minimizing the formation of degradation products and optimizing protein purification conditions. This result was further confirmed by western blot with anti-GST and anti-IRF-1 polyclonal antibodies. The functionality of GST-huIRF-1 was attained by elerophoretic mobility shift assay study as a clear band shifting showed with virus response element-Interferon beta (VRE-IFNß) promoter region. Taken together, the biological activity of purified GST-huIRF-1 was also optimized and confirmed by supershift assay concluded that GST-huIRF-1 interacts with the VRE motif of IFNß promoter that reflected to require for IFNß gene regulation. We describe a straightforward approach for the production of absolutely soluble and biologically active IRF-1 in E. coli. This method can be further used for the study of other recombinant proteins and this study will pave way for the analysis of IRF-1 function in vitro.

Randomized Trial to Compare Plasma Glucose Trends in Patients Undergoing Surgery for Supratentorial Gliomas under Maintenance of Sevoflurane, Desflurane, and Propofol.

BACKGROUND: Anesthetic agents influence the glycemic response by affecting the neuroendocrine surgical response or directly modifying pancreatic insulin release. Due to chances of neuronal damage, intraoperative hyperglycemia and hypoglycemia both are detrimental for patients undergoing neurosurgeries. Inhalational (sevoflurane and desflurane) and intravenous (propofol) agents have been found to raise intraoperative glucose levels in nonneurological surgeries. AIM: We aimed to compare the intraoperative glucose levels in supratentorial glioma surgeries under the maintenance of three anesthetic agents such as sevoflurane, desflurane, and propofol. MATERIALS AND METHODS: This randomized trial was conducted with 90 nondiabetic adults with supratentorial glioma. Thirty patients were allocated randomly to the three groups receiving sevoflurane, desflurane, and propofol. Baseline and hourly plasma glucose levels were recorded. Postoperatively, the time required to achieve an Aldrete score of 9 and complications were assessed. RESULTS: Baseline plasma glucose levels were 111.23 ± 11.67, 109.47 ± 19.75, and 111.7 ± 13.88 mg/dL (P = 0.84) in sevoflurance, desflurane, and propofol group, respectively. All of them showed an elevation of plasma glucose in relation to the time of surgery with variable trends. In the 4th and 5th h, the elevations in the inhalational groups (sevoflurane and desflurane) were significantly higher than the propofol group (P = 0.003 and 0.002, respectively). The time for achieving Aldrete's score of 9 was higher in the propofol group (P < 0.0001). No differences were observed in the duration of hospital stay or complications. CONCLUSIONS: Maintenance of anesthesia in nondiabetic patients showed clinically modest rise of plasma glucose which is higher in patients under sevoflurane and desflurane than under propofol. However, the immediate recovery was faster with inhalational agents compared to propofol-based anesthesia.

Ultrasound-guided Anterior Quadratus Lumborum Block for Postoperative Pain after Laparoscopic Pyeloplasty: A Randomized Controlled Trial.

BACKGROUND: Quadratus lumborum block (QLB) has provided adequate analgesia and lowered postoperative opioid requirement in comparison to controls for some urological surgeries. AIMS: The aim of this study was to assess the efficacy of postprocedure ultrasound-guided QLB in comparison to port-site infiltrations with local anesthetics (as control) in lowering postoperative pain after laparoscopic pyeloplasty. SETTINGS AND DESIGN: This was a prospective, single-blinded, randomized controlled trial. MATERIALS AND METHODS: Fifty-three adults undergoing laparoscopic pyeloplasty were randomly allocated to either anterior QLB group (n = 27) or port-site infiltration Group P (n = 26) with 20 mL of 0.5% ropivacaine. The primary outcomes were static and dynamic pain on the Visual Analog Scale (VAS) of 0-100 at the 30th min, 2nd, 6th, 12th, and 24th hour after surgery. The secondary outcomes were number of patients requiring rescue analgesics and having postoperative nausea or vomiting (PONV) in 24 hours after surgery. STATISTICAL ANALYSIS: Intergroup comparison of VAS was done with Student's t-test. Categorical data were analyzed using the Chi-square test. RESULTS: The static VAS scores were found to be significantly lower in QLB group at the 2nd, 6th, and 12th hour, and the dynamic VAS was lower at all time points after the 30th min in the QLB group. The number of patients requiring rescue analgesics were significantly lower in the QLB group (13 as compared to 21 in Group P; P = 0.015). The incidence of PONV was comparable. No other side effects were seen. CONCLUSION: Ultrasound-guided anterior QLB is more effective in comparison to traditional technique of port-site local anesthetic infiltration for providing analgesia after laparoscopic pyeloplasty.

Ultrasound-guided Bilateral Erector Spinae Plane Block for Postoperative Analgesia in Laparoscopic Cholecystectomy: A Randomized Controlled Trial.

BACKGROUND: Laparoscopic cholecystectomy (LC) is associated with moderate-to-severe pain in immediate postoperative period. Some patients even suffer from prolonged pain long after surgery. AIMS: The aim of present study is to determine the efficacy of ultrasound-guided bilateral erector spinae plane block (ESPB) in patients undergoing LC, time to ambulation after surgery, and incidence of prolonged pain up to 6 months later. SETTINGS AND DESIGN: This was a double-blinded prospective randomized controlled trial. MATERIALS AND METHODS: Eighty-five adults posted for elective LC were randomized to receive bilateral ESPB at T7 level with either 20 mL of 0.375% ropivacaine or 20 mL normal saline. Postoperative static and dynamic pain score as per the visual analog scale (VAS), intraoperative requirement of fentanyl, postoperative use of diclofenac, time to ambulation after surgery, and presence of any pain after surgery were noted. STATISTICAL ANALYSIS: Independent t-test and Mann-Whitney U-test were used for quantitative data, while Chi-square test was used for comparing qualitative data. RESULTS: Static and dynamic VAS scores were significantly lower in ESPB group (P < 0.05). Intraoperative fentanyl requirement (165 ± 30.72 - ESPB, 180.95 ± 29.12 - controls, P = 0.020) and number of patients requiring diclofenac (28/42 - ESPB, 37/42 - controls, P = 0.019) were lower, while number of patients ambulating by 4 hours (20/42 - ESPB, 9/42 - control, P = 0.012) were higher in ESPB group. Patients suffering from pain at 1 week (22/42 - ESPB and 34/42 - control, P = 0.005) and 1 month (9/42 - ESPB and 13/42 - control, P = 0.207) were lower in ESPB group. CONCLUSION: ESPB provides effective analgesia and early ambulation after LC. The benefit extends to 1 week thereafter.

Design, preparation and in vitro characterizations of fluconazole loaded nanostructured lipid carriers

Present study was aimed to prepare and characterize fluconazole loaded nanostructured lipid carriers (FLZ-NLCs) for the treatment of fungal infections. Fungal infections are tremendously widespread and are the often faced dermatological condition worldwide. FLZ-NLCs was prepared by ultrasonication emulsion technique using stearic acid (SA) as solid lipid, castor oil as liquid lipid and tween 20 as a surfactant. The mean diameter of optimized FLZ-NLCs were found to be 359.15 ± 9.83 nm. The drug content and entrapment efficiency of NLCs was found to be 102.97 ± 7.45% and 87 ± 0.59%, respectively. In vitro drug release studies of FLZ-NLCs showed 37.34 ± 2.08% drug release over a period of 72 h. The above studies confirmed the prepared FLZ-NLCs may be useful for the treatment of fungal infections.

In silico studies, synthesis and anticancer activity of novel diphenyl ether-based pyridine derivatives.

A series of novel 2-amino-4-(3-hydroxy-4-phenoxyphenyl)-6-(4-substituted phenyl) nicotinonitriles were synthesized and evaluated against HepG2, A-549 and Vero cell lines. Compounds 3b (IC50 16.74 ± 0.45 µM) and 3p (IC50 10.57 ± 0.54 µM) were found to be the most active compounds against A-549 cell line among the evaluated compounds. Further 3b- and 3p-induced apoptosis was characterized by AO/EB (acridine orange/ethidium bromide) nuclear staining method and also by DNA fragmentation study. A decrease in cell viability and initiation of apoptosis was clearly evident through the morphological changes in the A-549 cells treated with 3b and 3p when stained with this method. Fragmentation of DNA into nucleosomes was observed which further confirmed the cell apoptosis in cells treated with compound 3b. Flow cytometry studies confirmed the cell cycle arrest at G2/M phase in A549 cells treated with compound 3b. Further in silico studies performed supported the in vitro anticancer activity of these compounds as depicted by dock score and binding energy values.

Dysregulation of Δ4-3-oxosteroid 5ß-reductase in diabetic patients: Implications and mechanisms.

Aldo-keto reductase family 1 member D1 (AKR1D1) is a Δ4-3-oxosteroid 5ß-reductase required for bile acid synthesis and steroid hormone metabolism. Both bile acids and steroid hormones, especially glucocorticoids, play important roles in regulating body metabolism and energy expenditure. Currently, our understanding on AKR1D1 regulation and its roles in metabolic diseases is limited. We found that AKR1D1 expression was markedly repressed in diabetic patients. Consistent with repressed AKR1D1 expression, hepatic bile acids were significantly reduced in diabetic patients. Mechanistic studies showed that activation of peroxisome proliferator-activated receptor-α (PPARα) transcriptionally down-regulated AKR1D1 expression in vitro in HepG2 cells and in vivo in mice. Consistently, PPARα signaling was enhanced in diabetic patients. In summary, dysregulation of AKR1D1 disrupted bile acid and steroid hormone homeostasis, which may contribute to the pathogenesis of diabetes. Restoring bile acid and steroid hormone homeostasis by modulating AKR1D1 expression may represent a new approach to develop therapies for diabetes.

CancerPDF: A repository of cancer-associated peptidome found in human biofluids.

CancerPDF (Cancer Peptidome Database of bioFluids) is a comprehensive database of endogenous peptides detected in the human biofluids. The peptidome patterns reflect the synthesis, processing and degradation of proteins in the tissue environment and therefore can act as a gold mine to probe the peptide-based cancer biomarkers. Although an extensive data on cancer peptidome has been generated in the recent years, lack of a comprehensive resource restrains the facility to query the growing community knowledge. We have developed the cancer peptidome resource named CancerPDF, to collect and compile all the endogenous peptides isolated from human biofluids in various cancer profiling studies. CancerPDF has 14,367 entries with 9,692 unique peptide sequences corresponding to 2,230 unique precursor proteins from 56 high-throughput studies for ~27 cancer conditions. We have provided an interactive interface to query the endogenous peptides along with the primary information such as m/z, precursor protein, the type of cancer and its regulation status in cancer. To add-on, many web-based tools have been incorporated, which comprise of search, browse and similarity identification modules. We consider that the CancerPDF will be an invaluable resource to unwind the potential of peptidome-based cancer biomarkers. The CancerPDF is available at the web address http://crdd.osdd.net/raghava/cancerpdf/ .

Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists.

Farnesoid X receptor (FXR), a nuclear receptor mainly distributed in liver and intestine, has been regarded as a potential target for the treatment of various metabolic diseases, cancer and infectious diseases related to liver. Starting from two previously identified chalcone-based FXR antagonists, we tried to increase the activity through the design and synthesis of a library containing chalcones, flavones and chromenes, based on substitution manipulation and conformation (ring closure) restriction strategy. Many chalcones and four chromenes were identified as microM potent FXR antagonists, among which chromene 11c significantly decreased the plasma and hepatic triglyceride level in KKay mice.

A quality by design approach on polymeric nanocarrier delivery of gefitinib: formulation, in vitro, and in vivo characterization.

Gefitinib is an anticancer agent which acts by inhibiting epidermal growth factor receptor tyrosine kinase receptors. The aim of the present study was to prepare gefitinib nanosuspension. Gefitinib was encapsulated in Eudragit® RL100 and then dispersed in stabilizer solution, polyvinyl alcohol, and polyvinylpyrrolidone K30. Nanosuspension was prepared by using homogenization and ultrasonication techniques. The quality by design approach was also used in the study to understand the effect of critical material attributes (CMAs) and critical processing parameters (CPPs) on critical quality attributes and to improve the quality and safety of formulation. To study the effect of CMAs and CPPs, 23 full factorial design was applied. The particle size, polydispersity index, and zeta potential of the optimized solution were 248.20 nm, 0.391, and -5.62 mV, respectively. Drug content of the optimized nanoformulation was found to be 87.74%±1.19%. Atomic force microscopy studies of the optimized formulation confirmed that the prepared nanoparticles are smooth and spherical in nature. In vitro cytotoxicity studies of the nanosuspension on Vero cell line revealed that the formulation is nontoxic. The gefitinib nanosuspension released 60.03%±4.09% drug over a period of 84 h, whereas standard drug dispersion released only 10.39%±3.37% drug in the same duration. From the pharmacokinetic studies, half-life, Cmax, and Tmax of the drug of an optimized nanosuspension were found to be 8.65±1.99 h, 46,211.04±5,805.97 ng/mL, and 6.67±1.77 h, respectively. A 1.812-fold increase in relative bioavailability of nanosuspension was found, which confirmed that the present formulation is suitable to enhance the oral bioavailability of gefitinib.

Evaluation of efficacy of amikacin for attenuation of catheter-related bladder discomfort in patients undergoing percutaneous nephrolithotomy: A prospective, randomized, placebo-controlled, double-blind study.

CONTEXT: Catheter-related bladder discomfort (CRBD) is the most distressing symptom in patients due to intraoperative urinary catheterization. Amikacin significantly inhibits detrusor contraction evoked by prejunctional stimulation. AIMS: The aim of this study is to evaluate the efficacy of amikacin in prevention of CRBD in patients undergoing percutaneous nephrolithotomy. SETTINGS AND DESIGN: Study areas were operation theater and postanesthesia care unit of the Department of Anesthesiology, SGPGIMS, Lucknow. SUBJECTS AND METHODS: One hundred adult patients of either sex were randomly assigned into two groups of fifty each. Patients in control group received normal saline whereas patients in amikacin group received amikacin 10 mg/kg just before induction. Grading of CRBD was done as none, mild, moderate, and severe by a blinded observer at 0, 1, 6, 12, and 24 h after surgery. STATISTICAL ANALYSIS USED: Data were analyzed using Student's t-test and Chi-square test among groups. Incidence of CRBD was compared with Chi-square test whereas severity was analyzed by the test of proportions (Z-test). Visual analog score was compared using Mann-Whitney U-test for surgical site pain. RESULTS: Incidence of CRBD in control group was 66% as compared to 44% observed in amikacin group (P < 0.05). During intergroup comparison at different time points, incidence of CRBD was reduced at 1 and 6 h in the amikacin group (P < 0.05). Significant reduction in the severity of CRBD (moderate) was also observed at 1 h in the amikacin group (P < 0.05). At rest of the time points, there was no significant difference. CONCLUSIONS: Amikacin can significantly reduce the incidence and severity of CRBD in the first few hours after surgery.

Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump.

Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17ß-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α and farnesoid X receptor (FXR) and transrepression of BSEP by E2/ERα is an etiological contributing factor to intrahepatic cholestasis of pregnancy. Currently the mechanistic insights into such transrepression are not fully understood. In this study, the dynamics of coregulator recruitment to BSEP promoter after FXR activation and E2 treatment were established with quantitative chromatin immunoprecipitation assays. Coactivator peroxisome proliferator-activated receptor-γ coactivator-1 was predominantly recruited to the BSEP promoter upon FXR activation, and its recruitment was decreased by E2 treatment. Meanwhile, recruitment of nuclear receptor corepressor was markedly increased upon E2 treatment. Functional evaluation of ERα and ERß chimeras revealed that domains AC of ERα are the determinants for ERα-specific transrepression on BSEP. Further studies with various truncated ERα proteins identified the domains in ERα responsible for ligand-dependent and ligand-independent transrepression. Truncated ERα-AD exhibited potent ligand-independent transrepressive activity, whereas ERα-CF was fully capable of transrepressing BSEP ligand dependently in vitro in Huh 7 cells and in vivo in mice. Both ERα-AD and ERα-CF proteins were associated with FXR in the coimmunoprecipitation assays. In conclusion, E2 repressed BSEP expression through diminishing peroxisome proliferator-activated receptor-γ coactivator-1 recruitment with a concurrent increase in nuclear receptor corepressor recruitment to the BSEP promoter. Domains AD and CF in ERα mediated ligand-independent and ligand-dependent transrepression on BSEP, respectively, through interacting with FXR.

Transcriptional dynamics of bile salt export pump during pregnancy: mechanisms and implications in intrahepatic cholestasis of pregnancy.

UNLABELLED: Bile salt export pump (BSEP) is responsible for biliary secretion of bile acids, a rate-limiting step in the enterohepatic circulation of bile acids and transactivated by nuclear receptor farnesoid X receptor (FXR). Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent disorder among diseases unique to pregnancy and primarily occurs in the third trimester of pregnancy, with a hallmark of elevated serum bile acids. Currently, the transcriptional regulation of BSEP during pregnancy and its underlying mechanisms and involvement in ICP are not fully understood. In this study the dynamics of BSEP transcription in vivo in the same group of pregnant mice before, during, and after gestation were established with an in vivo imaging system (IVIS). BSEP transcription was markedly repressed in the later stages of pregnancy and immediately recovered after parturition, resembling the clinical course of ICP in human. The transcriptional dynamics of BSEP was inversely correlated with serum 17ß-estradiol (E2) levels before, during, and after gestation. Further studies showed that E2 repressed BSEP expression in human primary hepatocytes, Huh 7 cells, and in vivo in mice. Such transrepression of BSEP by E2 in vitro and in vivo required estrogen receptor α (ERα). Mechanistic studies with chromatin immunoprecipitation (ChIP), protein coimmunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC) assays demonstrated that ERα directly interacted with FXR in living cells and in vivo in mice. CONCLUSION: BSEP expression was repressed by E2 in the late stages of pregnancy through a nonclassical E2/ERα transrepressive pathway, directly interacting with FXR. E2-mediated repression of BSEP expression represents an etiological contributing factor to ICP and therapies targeting the ERα/FXR interaction may be developed for prevention and treatment of ICP.

Influence of medium constituents on the biosynthesis of cephalosporin-C

Acremonium chrysogenum NCIM 1069 was used for the biosynthesis of cephalosporin-C (CPC) in batch mode of cultivation. The effect of different medium constituents for better yield of CPC was thoroughly investigated. From the results of the fermentation, it was found that ammonium sulphate as inorganic nitrogen source and methionine at the concentration of 0.4 percent are most suitable for higher yield of antibiotic. The variation in the C/N ratio on the biosynthesis of CPC showed that a C/N ratio of 8.0 is most suitable for maximum production of CPC